The present invention relates to dietary supplements and medical foods for treating fatigue-related syndromes. The compositions of the present invention include rosemary.
In 1948, the World Health Organization defined health as not only the absence of disease, but also the presence of physical, mental, and social well-being. (Constitution of the World Health Organization. In: World Health Organization, Handbook of Basic Documents. 5th ed. Geneva: Palais des Nations, 3-20 (1952)). The status of a patient""s physical, mental, and social functioning is often referred to in the literature as quality-of-life and is used as a measure of health outcome. In the past 25 years, there has been a nearly exponential increase in the evaluation of quality-of-life as a technique of clinical research as a component of determining clinical benefit from an intervention protocol. For example, in 1973, only five articles listed quality-of-life as a key word in the Medline database, whereas in the subsequent four years there were successively 195,273,490, and 1,252 such articles. (Testa MA and Simonson DC, N Eng J Med. 334:835-840 (1996). In 1998, approximately 3,724 articles listed quality-of-life as a key word. Thus, the health outcome, or quality-of-life, associated with a clinical intervention has been recognized as an important tool in measuring effectiveness and costs of medical care. (Wilson IB and Cleary PD., JAMA., 273:59-65 (1995)).
Extensive research has resulted in the development of instruments that measure health outcome using quality-of-life tools that follow academically well-established and statistically validated psychometric principles. (Ware J E Jr., J Chronic Dis., 40:473-480 (1987); Spilker B., Quality of Life and Pharmacoeconomics in Clinical Trials, 2nd ed. Philadelphia, Pa: Lippincott-Raven Co; 1995.) One such tool is the SF-36 (Short form-36), which has been widely used in clinical trials and in clinical practice to assess health outcome. (Clancy CM and Eisenberg J M, Science, 282:245-246 (1998)). The SF-36 was derived from the Medical Outcomes Study, which involved 11,336 patients from 523 different clinical sites. (Ware J E, Sherbourne C D, Davies A R. Developing and testing the MOS 20-item short-form health survey. In: Stewart AL and Ware J E, eds., Measuring functioning and well-being: The Medical Outcomes Study approach. Durham, N.C.: University Press, 277-290 (1992); Ware J E. SF-36 Health Survey: manual and interpretation guide. Boston, Mass.: Nimrod Press; 2:1-3:22 (1993)). The validity and reliability of the SF-36 has been proven in several studies in which researchers tested internal consistency, within subject reliability, and differentiation between patient populations. (McHorney CA, et al., Medical Care, 31:247-263 (1993); McHorney CA, et al., Medical Care, 30:S253-S265 (1992); Jenkinson C, et al., Br Med J., 306:1436-1440 (1993); Brazier J E, et al., Br Med J. 305:160-164 (1992)). The SF-36 has been shown to predict the course of depression during a two-year study, and to be lower overall in patients who experience chronic health disorders. (Wells K B, et al., Archives General Psychiatry, 49:788-794 (1992); Schlenk E A, et al., Quality of Life Res., 7:57-65 (1998)).
The SF-36 is a 36-item questionnaire that assesses eight dimensions of health outcome: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Results from the questionnaire can be reported as a relative number on a scale of 0 to 100, in which 100 is the highest or most functional and 0 is the most compromised for that category of functioning. A summary of the meaning of high and low scores for each category is shown-in Table 1.
The latter half of the twentieth century has been characterized by an increasing prevalence of chronic disorders. Indeed, seven of the ten leading causes of death in the USA are chronic in nature, accounting for 72% of the deaths from all causes. (National Center for Health Statistics. Health, United States, 1995. Hyattsville, Md.: Public Health Service, 1995.) Chronic disorders such as rheumatic disorders, chronic pain, and fatigue contribute to the 6% of the population that is impaired to some extent in the conduct of major life activities such as work, school, and self-care. (US Department of Health and Human Services, Public Health Service. Healthy People 2000: National Health Promotion and Disease Prevention Objectives. Hyattsville, Md.: Public Health Service; 1991.) Health care use also appears to be substantial for patients with chronic conditions. For example, patients with chronic fatigue syndrome (CFS), fibromyalgia (FM), and multiple chemical sensitivities (MCS) have been shown to visit medical care facilities on average 22.1, 39.7, and 23.3 times per year, respectively. (Buchwald D, Garrity D., Arch Intern Med., 154:2049-2053 (1994)).
In chronic conditions such as rheumatic disorders, fatigue and energy-deficit disorders, and chronic pain, biological and physiological factors have an inconsistent relationship to symptoms. (Wilson IB, Cleary PD., JAMA, 273:59-65 (1995)). Therefore, they are difficult to measure by laboratory values. In fact, in clinical practice, anywhere from 30% to 80% of patients who see a physician may have conditions for which no physiological or organic cause is found after routine investigation. (Wilson IB and Cleary P D, JAMA, 273:59-65 (1995)).
For example, the term fibromyalgia (FM) refers to an illness whose major characteristics are widespread chronic pain and the physical finding of pain in specifically located tender points. (Wolfe F, et al., The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis Rheumatology, 33:160-172 (1990)). Fibromyalgia patients also commonly report morning stiffness, fatigue, and sleep disturbances. A patient presenting with fibromyalgia sometimes reports peripheral athralgias, which can be confused with rheumatoid arthritis. (Goldenberg D L., Current Opinions in Rheumatology, 5:199-208 (1993)). However, fibromyalgia is commonly accepted in the field as pain not associated with inflammation nor joint dysfunction, whereas athralgias are considered inflammatory joint disorders.
Another example of a chronic condition is xe2x80x9cchronic fatigue syndromexe2x80x9d (CFS). Clinical diagnosis of CFS requires that the patient show evidence of fatigue lasting beyond 6 months, as well as having eight or more of the following minor symptoms: fever, sore throat, myalgia, muscle weakness (which may be exacerbated by exercise), athralgia, lymphadenopathy, sleep disturbance, headaches, acute or subacute onset, and neuropsychological symptoms. (Holmes G P, et al., Ann Intern Med., 108:387-389 (1988)). Other chronic conditions include idiotypic fatigue, myofascial pain syndrome, for which no definition exists, as well as autoimmune disorders, asthma, and gastrointestinal disorders such as irritable bowel syndrome.
In these chronic conditions, pain and fatigue are often suffered over many years without correlation to a diagnosable or definable acute or chronic disease. Therefore, without anatomical or physical correlation, a patient""s response to therapy must be monitored by measuring the level of symptoms they report over a period of time. The MOS SF-36 questionnaire is particularly suited to this type of analysis. For example, patients with chronic disorders such as fibromyalgia have been reported to score lower than the norm in several categories of the MOS SF-36, including bodily pain, role-physical, role-emotional, and vitality (Table 2 where numbers in brackets represent standard deviations).
The data presented in Table 2 are from Ware J E., SF-36 Health Survey: manual and interpretation guide. Boston, Mass.: Nimrod Press; 2:1-3:22 (1993); Schlenk EA, et al., Health-related quality of life in chronic disorders: a comparison across-studies using the MOS SF-36, Quality Life Research, 7:57-65 (1998)).
Although similarities in different categories of the MOS can be observed, data from patients who experience chronic conditions suggests that these patients may show higher variability when analyzing individual MOS categories than with the PCS and MCS summary scores. This variability may result from the frequent coexistence of chronic conditions. For example, it has been shown that 70% of patients with fibromyalgia also experience symptoms of irritable bowel syndrome (IBS), whereas only 10% of control patients experience IBS symptoms. (Veale D, et al., Br J Rheumatol., 30:220-222 (1991)). Fibromyalgia patients have also been reported to shown similar symptoms as CFS.
Taking these considerations into accounts, Ware et al. have used principal component analysis on the MOS SF-36 data collected from 2,474 subjects from the U.S. general population to derive summary scores for the eight categories shown above. (Ware J E Jr., Kosinski M, Keller S D. SF-36 Physical and Mental Health Summary Scales: A user""s manual. Boston, Mass.: The Health Institute, New England Medical Center; 3:1-4:6 (1994)). The Physical Component Summary (PCS) and Mental Component Summary (MCS) provide two reliable, reproducible scores for the physical and mental health, respectively. The PCS and MCS scores are converted to a scale of 0 to 100, in which 50 is the mean for the U.S. population.
This analysis of the MOS data takes into account the range of symptoms seen with the chronic condition and reduces the variability from individual patient differences. Low scores on the PCS indicate substantial limitations in self care, physical, social, and role activities, severe bodily pain, frequent tiredness, and health generally rated as poor, whereas high scores indicate no physical limitations, high energy level, and health generally rated as excellent. Low scores on the MCS indicate frequent psychological distress, substantial social and role disability due to emotional problems, and/or health generally rated as poor, whereas high scores indicate frequent positive affect and absence of psychological distress and limitations in usual social and role activities. Table 3 shows relative PCS and MCS scores for various chronic health conditions as compared to U.S. population normative data. Standard deviation is abbreviated as S.D.
It has been the experience of the present inventors that many patients with fatigue-related syndromes, such as fibromyalgia, respond with only moderate improvement to dietary programs. Further, this response has been variable, with a large percentage of patients with fatigue-related syndromes not responding to dietary changes at all. Pharmaceutical approaches, such as non-steroidal anti-inflammatories or anti-depressants have been investigated for fibromyalgia with moderate but variable response. In particular, research on the use of anti-inflammatories to treat fatigue-related syndromes has not shown significant improvement above placebo.
Consequently, there is a need for a dietary supplement and/or medical food that ameliorates at least one of the symptoms, preferably all of the symptoms of a fatigue-related syndrome, such as fibromyalgia, idiotypic fatigue, multiple chemical sensitivity and chronic fatigue syndrome, by way of example. In particular, there is a need for a dietary supplement and/or medical food that improves both the physical and mental functioning of a person suffering from a fatigue-related syndrome.
The present invention provides dietary supplements, medical foods and methods effective to ameliorate at least one of the symptoms, preferably all of the symptoms, of a fatigue-related syndrome, such as fibromyalgia, idiotypic fatigue, multiple chemical sensitivity and chronic fatigue syndrome. Preferred dietary supplements and medical foods of the present invention improve both the physical and mental functioning of a person suffering from a fatigue-related syndrome, such as fibromyalgia, idiotypic fatigue, multiple chemical sensitivity and chronic fatigue syndrome.
The dietary supplements of the present invention are compounded for the amelioration of a fatigue-related syndrome and include rosemary, curcumin and at least one component selected from the group consisting of quercetin and rutin. A presently preferred dietary supplement of the invention includes rosemary, curcumin and quercetin. The dietary supplements of the present invention are preferably compounded in a daily dose that includes rosemary in an amount of from about 180 mg to about 220 mg; curcumin in an amount of from about 360 mg to about 440 mg; quercetin, if utilized, in an amount of from about 360 mg to about 440 mg; and rutin, if utilized, in an amount of about 360 mg to about 440 mg.
Additionally, presently preferred dietary supplements of the invention may include at least one component selected from the group consisting of limonene, preferably D-limonene, hesperidin and ginger. The dietary supplements of the present invention are preferably compounded in a daily dose that can include one or more of the following components: limonene in an amount of from about 180 mg to about 220 mg; hesperidin in an amount of from about 360 mg to about 440 mg; and ginger in an amount of from about 180 mg to about 220 mg. The dietary supplements of the present invention optionally include at least one vitamin and at least one non-vitamin antioxidant.
The present invention also provides medical foods compounded for the amelioration of a fatigue-related syndrome. The medical foods of the present invention include rosemary, at least one macronutrient selected from the group consisting of protein, carbohydrate and fat, and at least one member of the group consisting of quercetin, curcumin and rutin. A presently preferred medical food of the invention includes rosemary, curcumin and quercetin. The medical foods of the present invention are preferably compounded in a daily dose that includes rosemary in an amount of from about 180 mg to about 220 mg; curcumin, if utilized, in an amount of from about 360 mg to about 440 mg; quercetin, if utilized, in an amount of from about 360 mg to about 440 mg; and rutin, if utilized, in an amount of about 360 mg to about 440 mg.
Additionally, presently preferred medical foods of the invention may include at least one component selected from the group consisting of limonene, preferably D-limonene, hesperidin and ginger. The medical foods of the present invention are preferably compounded in a daily dose that can include one or more of the following components: limonene in an amount of from about 180 mg to about 220 mg; hesperidin in an amount of from about 360 mg to about 440 mg; and ginger in an amount of from about 180 mg to about 220 mg. The medical foods of the present invention optionally include at least one vitamin and at least one non-vitamin antioxidant.
Macronutrients included in the medical foods of the present invention include protein, carbohydrates and fat. The protein is preferably obtained from a cereal grain that is gluten-free, or substantially gluten-free. The presently preferred protein source is a hypoallergenic rice protein concentrate, suitably prepared as disclosed in U.S. Pat. No. 4,876,096, incorporated herein by reference. A daily dose of the medical foods of the present invention include protein in an amount of from about 25 g to about 35 g. Carbohydrates are provided as rice fiber, bran and/or flour, or equivalent gluten-free or substantially gluten-free grain fiber, bran and/or flour. Carbohydrate can also be provided as rice syrup solids which contain approximately 70 to 90 percent by weight of high molecular weight dextran, or as equivalent gluten-free or substantially gluten-free grain syrup solids. A daily dose of the medical foods of the present invention include carbohydrate in an amount of from about 43 g to about 69 g. Fats are preferably provided as medium chain triglycerides, preferably in combination with canola oil. Canola oil can be substituted with nutritionally equivalent oils, such as flaxseed oil and safflower oil. Medium chain triglycerides useful in the compositions of the present invention include a fatty acid moiety having an 8 to 14 carbon atom backbone, and can be derived from, for example, coconut oil and related tropical oils. A daily dose of the medical foods of the present invention include fats in an amount of from about 3 g to about 8 g.
Presently preferred medical foods of the invention may also include at least one vitamin, or vitamin precursor. Preferred vitamins possess antioxidant properties and include vitamins A, C and E, and/or their biochemical precursors. Presently preferred medical foods of the invention also include at least one trace element, preferably selected from the group consisting of zinc, manganese and selenium. Presently preferred medical foods of the invention also may include at least one additional antioxidant selected from the group consisting of carotenoids, N-acetylcysteine and L-glutamine. The presently preferred amounts of preferred vitamins, trace elements, non-vitamin antioxidants and other components that can be included in the medical foods of the invention are set forth in Table 4.
In addition, the present invention provides methods for treating fatigue-related syndromes. In one embodiment, the methods of the present invention include the step of administering to a person suffering from a fatigue-related syndrome an effective amount of a dietary supplement of the present invention. Preferably the dietary supplement is administered at least once per day. In another embodiment, the methods of the present invention include the step of administering to a person suffering from a fatigue-related syndrome an effective amount of a medical food of the present invention. Preferably the medical food is administered at least once per day.
The present invention provides dietary supplements, medical foods and methods effective to ameliorate at least one of the symptoms of a fatigue-related syndrome. Preferred dietary supplements and medical foods of the present invention improve both the physical and mental functioning of a person suffering from a fatigue-related syndrome. As used herein, the term xe2x80x9cfatigue-related syndromexe2x80x9d refers to a medical condition characterized by chronic fatigue. Typically, a person suffering from a fatigue-related syndrome exhibits other symptoms in addition to chronic fatigue, such as non-specific joint pain, muscle pain, headache, sleep disturbance, low-grade fever, lymphadenopathy, post-exertional fatigue, pharyngitis, impaired memory or concentration, and muscle weakness. As the term is used herein, a xe2x80x9cfatigue-related syndromexe2x80x9d does not include inflammation as a predominant symptom. By way of non-limiting example, the term xe2x80x9cfatigue-related syndromexe2x80x9d includes idiotypic fatigue, fibromyalgia, multiple chemical sensitivity and chronic fatigue syndrome. Presently preferred dietary supplements, medical foods and methods of the present invention are especially effective when used to treat fibromyalgia.
The compositions of the present invention include rosemary, curcumin (always present in the dietary supplements, optionally present in the medical foods) and at least one component selected from the group consisting of quercetin and rutin. Preferably rosemary is utilized as an extract of ground rosemary leaves; curcumin is utilized as a tumeric extract in powder form; quercetin is utilized as either pure quercetin or as a quercetin glycoside (e.g., rutin). The compositions of the present invention may preferably include ginger, limonene and hesperidin. Ginger is preferably utilized as a concentrate of a ginger root extract. Any pure, or substantially pure, form of limonene or hesperidin is useful in the compositions of the present invention.
Rosemary contains the flavonoids carnosol, carnosic acid, rosmanol and ursolic acid and the compositions of the present invention can be supplemented with one or more of the foregoing flavonoids. Ginger contains 6-gingerol, zingerone and 6-shogaol. The compositions of the present invention can be supplemented with one or more of the foregoing ginger components.
The medical foods of the present invention include a protein source, preferably hypoallergenic rice protein extract, suitably prepared as described in U.S. Pat. No. 4,876,096, incorporated herein by reference. The hypoallergenic rice protein extract is preferably fortified with at least one of the following amino acids: L-lysine, L-threonine and L-cysteine. In a presently preferred embodiment, the medical foods of the present invention are fortified with L-lysine and L-threonine in amounts of 6.3% and 0.28% of the weight of rice protein, respectively.
Both the dietary supplements and medical foods of the present invention are preferably used in powder form which can be dissolved in a liquid suitable for human consumption, such as water or a fruit juice. The dietary supplements and medical foods of the present invention can, however, be utilized in any suitable form, such as a solid bar, as a paste, gel, tablet, capsule or liquid.
Typically, the dietary supplements and medical foods of the present invention are preferably administered two times per day, preferably once in the morning and once in the afternoon. A typical treatment regime for the dietary supplements or medical foods will continue for four to eight weeks. Depending on such factors as the medical condition being treated and the response of the patient, the treatment regime may be extended. A medical food of the present invention will typically be consumed in two servings per day as either a meal replacement or as a snack between meals. A serving size for a medical food of the present invention will preferably be in the range of from about 45 grams to about 60 grams and will provide from about 180 calories to about 220 calories to the consumer. In a presently preferred treatment regime a person in need of treatment is provided with two servings of a medical food of the present invention per day. A presently preferred serving size is about 52 grams of powdered medical food which delivers about 200 calories to the consumer.
Suitable ranges for each component preferably included in a medical food in accordance with the present invention are set forth in Table 4 of Example 1. For a dietary supplement compounded in accordance with the present invention, the same ranges of specific ingredients to be included(e.g. Rosemary, Curcurmin, Quercetin, etc.) are utilized. The following examples merely illustrate a preferred embodiment now contemplated for practicing the invention, but should not be construed to limit the invention.